![]() In fact, patients still exhibit motor function deficits and the muscle atrophy that characterizes SMA cannot be rescued. While treated patients show improvements in neuromotor tone and lifespan, ongoing loss of SMN function and presence of neuromuscular symptoms remain. Nusinersen is an AntiSense Oligonucleotide (ASO) that binds to a specific sequence in the SMN2 RNA altering its splicing pattern to produce a functional SMN protein only in the central nervous system Risdiplam works by correcting SMN2 splicing preventing the removal of exon 7 from the mature mRNA Zolgensma is an adeno-associated viral vector (AAV) gene therapy that delivers the SMN transgene and produces the full-length functional SMN protein. While all these 3 therapies aim at SMN restoration, Nusinersen and Risdiplam target SMN2, whereas Zolgensma targets SMN1. The existence of SMN2 constitutes the rationale for two of the three recently approved gene treatments for SMA. Only 10–20% of SMN2 mRNA originates a full-length stable SMN protein that can rescue SMN1 loss. However, this gene is aberrantly spliced originating an unstable, degraded SMN protein. In most tissues, a paralogue human gene ( SMN2) exists. The motor neurons of the anterior horns of the spinal cord degenerate in SMA patients, resulting in fatigue, atrophy of the proximal muscles, and paralysis of respiratory muscles. Spinal muscular atrophy (SMA) is a severe motoneuron disease caused by a genetic defect in the SMN1 gene encoding for the survival motoneuron protein SMN1. Thus, targeting muscle mitochondrial dysfunction in SMA may complement the current gene therapy. Amniotic fluid stem cells transplantation that corrects the SMN knockout mouse myopathic phenotype restored mitochondrial morphology and expression of mitochondrial genes. Albeit levels of proteins that mark mitochondria for mitophagy were increased, morphologically deranged mitochondria with impaired complex I and IV activity and respiration and that produced excess reactive oxygen species accumulated in Smn1 knockout muscles, because of the lysosomal dysfunction highlighted by the transcriptional profiling. ![]() Expression profiling of single myofibers from a muscle specific Smn1 knockout mouse model revealed down-regulation of mitochondrial and lysosomal genes. Here we show that SMN loss in mouse skeletal muscle leads to accumulation of dysfunctional mitochondria. These therapies primarily target motor neurons, but SMN1 loss has detrimental effects beyond motor neurons and especially in muscle. The approved gene therapies for spinal muscular atrophy (SMA), caused by loss of survival motor neuron 1 (SMN1), greatly ameliorate SMA natural history but are not curative.
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